1. Field of the Invention
This invention relates to 1-azatricyclic-4-benzylpiperazines, and to compounds that bind to dopamine receptors. This invention also relates to pharmaceutical compositions comprising such compounds and also to the treatment of central nervous system (CNS) diseases, particularly the treatment or prevention of psychotic disorders such as schizophrenia. Additionally this invention relates to the use of compounds as probes for the localization of dopamine receptors in tissue sections.
2. Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D.sub.2 receptors in the striatal region of the brain. The dopamine D.sub.4 receptor subtype has been identified and cloned. Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D.sub.4 receptor may play a major role in the etiology of schizophrenia. The dopamine D.sub.4 receptor shares sequence homology with dopamine D.sub.2 and D.sub.3 receptors, however the D.sub.4 receptor possesses a unique pharmacological profile. Selective D.sub.4 antagonists, including the marketed antipsychotic chlozapine, are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics. Compounds that possess a 10-fold or more higher affinity for dopamine D.sub.4 receptors than D.sub.2 receptors are considered particularly desirable as antipsychotics.
Since dopamine D.sub.4 receptors are concentrated in the limbic system which controls cognition and emotion, compounds which interact with these receptors have utility in the treatment of cognitive disorders. Such disorders include the cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders involving memory impairment or attention deficit disorder can also be treated with compound that interact specifically with the dopamine D.sub.4 receptor subtype.